CN117209538A - Deuterated matter for degrading EGFR and application of deuterated matter in medicine - Google Patents

Deuterated matter for degrading EGFR and application of deuterated matter in medicine Download PDF

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CN117209538A
CN117209538A CN202310519238.4A CN202310519238A CN117209538A CN 117209538 A CN117209538 A CN 117209538A CN 202310519238 A CN202310519238 A CN 202310519238A CN 117209538 A CN117209538 A CN 117209538A
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acid
compound
deuterated
pharmaceutically acceptable
acceptable salt
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张晨
王健民
黄正刚
黄安邦
李瑶
严庞科
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Tibet Haisike Pharmaceutical Co ltd
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Abstract

The invention relates to a compound shown in a general formula (I) or deuterated compound, stereoisomer, tautomer, hydrate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, an intermediate and a preparation method thereof, and application of the compound or the deuterated compound, stereoisomer, tautomer, hydrate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof in preparation of medicines for treating diseases related to inhibiting or degrading EGFR.

Description

Deuterated matter for degrading EGFR and application of deuterated matter in medicine
Technical Field
The invention relates to a compound shown in a general formula (I) or deuterated compound, stereoisomer, tautomer, hydrate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, an intermediate and a preparation method thereof, and application of the compound or the deuterated compound, stereoisomer, tautomer, hydrate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof in preparation of medicines for treating diseases related to inhibiting or degrading EGFR.
Background
Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein tyrosine kinase that acts as a receptor for EGF family members triggering EGFR signaling pathways in human epithelial cells, thereby regulating cell proliferation, invasion, metastasis, apoptosis and angiogenesis (Nat. Rev. Cancer,2007,7,169-181;Expert Opin.Ther.Targets,2012,16,15-31.). Overexpression, mutation or amplification of the EGFR gene in humans results in an abnormally increased EGFR activity, which can lead to the production of many malignant tumors such as esophageal cancer, glioblastoma, anal cancer, head and neck epithelial cancer, breast cancer, lung cancer, in particular non-small cell lung cancer (NSCLC) (Cells, 2019,8,350-361).
PROTAC (proteolysis targeting chimera) is a double-function compound capable of simultaneously combining target protein and E3 ubiquitin ligase, and the compound can be recognized by a proteasome of a cell to cause degradation of the target protein, so that the content of the target protein in the cell can be effectively reduced. The use of the PROTAC technology for the treatment of various diseases has been made possible by the introduction of ligands capable of binding to different targeting proteins in the PROTAC molecule, which has received a great deal of attention in recent years (ACS chem. Biol.2017,12,892-898;Drug Discovery Today Technol.2019,31,15-27.).
Development of novel procac drugs that bind EGFR protein and E3 ubiquitin ligase for the treatment of diseases associated with EGFR protein would be promising for application.
Disclosure of Invention
The invention aims to provide a compound capable of inhibiting and degrading EGFR, and preparation and application thereof.
The invention provides a compound or deuterated compound, stereoisomer, tautomer, hydrate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, wherein the compound is selected from the compounds shown in the general formula (I)
R 1a 、R 1b 、R 1c 、R 1d 、R 1e 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 3 、R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f 、R 4g 、R 4h 、R 4i 、R 4j 、R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g 、R 5h 、R 5i 、R 6a 、R 6b 、R 7a 、R 7b 、R 7c 、R 7d 、R 7e 、R 7f 、R 7g 、R 7h 、R 8a 、R 8b 、R 8c 、R 9a 、R 9b 、R 9c 、R 9d 、R 9e Each independently is selected from H or D, provided that there are at least 1 selected from D.
The invention provides a compound shown in the specification or deuterated, stereoisomer, tautomer, hydrate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof,
。
in an embodiment of the invention, wherein the pharmaceutically acceptable salt is selected from the group consisting of maleic acid, fumaric acid, hydrohalic acid (preferably hydrobromic acid and hydrochloric acid), sulfuric acid, phosphoric acid, L-tartaric acid, citric acid, L-malic acid, hippuric acid, D-glucuronic acid, glycolic acid, mucic acid, succinic acid, lactic acid, orotic acid, pamoic acid, malonic acid, gentisic acid, salicylic acid, oxalic acid or glutaric acid.
The invention relates to a pharmaceutical composition, which comprises the compound or deuterated compound, stereoisomer, tautomer, hydrate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof and a pharmaceutically acceptable carrier.
The invention relates to application of the compound or deuterated, stereoisomer, tautomer, hydrate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic thereof in preparing medicaments for treating diseases related to EGFR inhibition or degradation, preferably in preparing medicaments for treating tumors, preferably non-small cell lung cancer.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I referred to in the groups and compounds of the invention each include their isotopic condition, and the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C、 13 C and C 14 Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include 16 O、 17 O and 18 isotopes of O, sulfur include 32 S、 33 S、 34 S and 36 isotopes of S, nitrogen include 14 N and 15 isotopes of N, fluorine include 17 F and F 19 Isotopes of F, chlorine include 35 Cl and Cl 37 Isotopes of Cl, bromine include 79 Br and 81 Br。
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl may be, but is not necessarily, substituted with F, and is intended to include both cases where the alkyl is substituted with F and cases where the alkyl is not substituted with F.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reaction with a non-toxic inorganic or organic base.
"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance that is added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.
"prodrug" means a compound of the invention which is converted into a biologically active form by in vivo metabolism. Prodrugs of the invention are prepared by modifying amino or carboxyl groups in the compounds of the invention, which modifications may be removed by conventional procedures or in vivo to give the parent compound. When the prodrugs of the invention are administered to a mammalian subject, the prodrugs are cleaved to form the free amino or carboxyl groups.
"co-crystals" refers to crystals of Active Pharmaceutical Ingredient (API) and co-crystal former (CCF) that are bound by hydrogen bonds or other non-covalent bonds, wherein the pure states of the API and CCF are both solid at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.
"animal" is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.
"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
"tautomer" refers to a functional group isomer produced by rapid movement of an atom in a molecule at two positions, such as keto-enol isomers and amide-imine alcohol isomers.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group, and cases where the heterocyclic group is not substituted with an alkyl group.
“IC 50 "is the concentration of drug or inhibitor required to inhibit half of a given biological process (or a component of the process such as an enzyme, receptor, cell, etc.).
Detailed Description
The following examples illustrate the technical aspects of the present invention in detail, but the scope of the present invention is not limited thereto. The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art starting from commercially available chemicals and/or compounds described in the chemical literature. "commercially available chemicals" are obtained from regular commercial sources and include: taitan technology, an Naiji chemistry, shanghai de moer, chengdu Kelong chemical, shaoguan chemical technology, nanjing medical stone, ming Kangde and Budweiser technologies.
The structure of the compound is obtained by Nuclear Magnetic Resonance (NMR) or (sum) mass spectrometry(MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was performed using a (Bruker Avance III and Bruker Avance 300) magnetonuclear apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS);
MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18X14.6mm, 3.5. Mu.M);
the thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm;
column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.
Example 1:5- (4- ((1- (4- ((5-bromo-4- ((4-cyclopropyl-2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-amino) -5- (tridecylmethoxy) -2- (1- (tridecylomethyl) -1H-pyrazol-4-yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 1)
5-(4-((1-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-(methoxy-d3)-2-(1-(methyl-d3)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
The first step: (2-amino-5-bromophenyl) dimethylphosphine oxide (1H-1)
(2-amino-5-bromophenyl)dimethylphosphine oxide
4-bromo-2-iodoaniline (0.5 g,1.68 mmol), dimethylphosphine oxide (0.13 g,1.68 mmol), xant-Phos (4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, 49mg,0.084 mmol) and anhydrous potassium phosphate (0.46 g,2.18 mmol) were added sequentially to 10mL of 1, 4-dioxane, and palladium acetate (19 mg,0.084 mmol) was added with stirring. The mixture was replaced with nitrogen three times and stirred at 80℃for 5h. Cooled to room temperature, filtered, the filter cake was washed with 20mL ethyl acetate and the filtrates were combined. The filtrate was concentrated under reduced pressure, and 5mL of methyl tert-butyl ether was added to the residue to pulp, followed by filtration and drying of the cake to give 1H-1 (0.3 g, yield: 72%).
LCMS m/z＝248.1[M+H] + 。
And a second step of: (2-amino-5-cyclopropylphenyl) dimethylphosphine oxide (1H-2)
(2-amino-5-cyclopropylphenyl)dimethylphosphine oxide
1H-1 (2.3 g,9.27 mmol) and cyclopropylboronic acid (2.39 g,27.81 mmol) were dissolved in 20mL dioxane and 4mL water, then tricyclohexylphosphine (0.52 g,1.85 mmol), palladium acetate (0.21 g,0.93 mmol) and potassium phosphate (7.87 g,37.08 mmol) were added thereto, nitrogen was replaced three times, reacted at 100℃for 24 hours, cooled to room temperature, the reaction solution was poured into water, and ethyl acetate was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give 1H-2 (1.26 g, yield 65%).
1 H NMR(400MHz,CDCl 3 )δ6.94(d,1H),6.88-6.80(m,1H),6.63-6.57(m,1H),1.82-1.71(m,7H),0.91-0.83(m,2H),0.59-0.51(m,2H)。
And a third step of: (2- ((5-bromo-2-chloropyrimidin-4-yl) amino) -5-cyclopropylphenyl) dimethylphosphine oxide (1H)
(2-((5-bromo-2-chloropyrimidin-4-yl)amino)-5-cyclopropylphenyl)dimethylphosphine oxide
Compound 1H-2 (0.26 g,1.24 mmol), 5-bromo-2, 4-dichloropyrimidine (0.57 g,2.48 mmol) was dissolved in 5mL NMP, DIPEA (190 mg,1.49 mmol) was added, stirred for 2H at 120℃to room temperature, water was added to the mixture, filtered, the cake was dried under reduced pressure, purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) =10/1-0/10), the residue was slurried with a mixed solvent of ethyl acetate/petroleum ether (10 mL, V/V=1/2), filtered, and the cake was dried under reduced pressure to give 1H (0.28 g, yield: 56%).
1 H NMR(400MHz,CDCl 3 )δ11.20(s,1H),8.45-8.39(m,1H),8.30(s,1H),7.24-7.19(m,1H),7.06-7.00(m,1H),1.93–1.79(m,7H),1.05-0.96(m,2H),0.78-0.65(m,2H)。
Fourth step: 1-bromo-2-fluoro-4- (tridecylmethoxy) -5-nitrobenzene (1A)
1-bromo-2-fluoro-4-(methoxy-d3)-5-nitrobenzene
4-bromo-5-fluoro-2-nitrophenol (2.36 g,10 mmol) was dissolved in 20mL DMF and potassium carbonate (2.76 g,20 mmol) and deuterated iodomethane-d were added 3 (2.90 g,20 mmol) was reacted at 45℃for 2h. Cooled to room temperature, the reaction mixture was diluted with 30mL of water, suction filtered under reduced pressure, and the cake was dried to give 1A (2.51 g, yield: 99%).
LCMS m/z＝252.9[M+H] +
1 H NMR(400MHz,DMSO-d 6 )δ8.34(d,1H),7.54(d,1H).
Fifth step: 4- ((1- ((benzyloxy) carbonyl) piperidin-4-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester (1A-1)
tert-butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate
4-formyl-N-Cbz-piperidine (2.47 g,10 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.86 g,10 mmol) were mixed in dichloromethane (100 mL), acetic acid (1.2 g,20 mmol) and sodium triacetoxyborohydride (4.24 g,20 mmol) were added sequentially and stirred overnight at room temperature. After addition of 100mL of methylene chloride and 50mL of 1n aqueous sodium hydroxide solution, the layers were separated, the organic layer was dried under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate/petroleum ether (V/V) =10/1-1/1) to give compound 1A-1 (3.54 g, yield: 85%).
LCMS m/z＝418.2[M+H] +
Sixth step: 4- (piperidin-4-ylmethyl) piperazine-1-carboxylic acid tert-butyl ester (1A-2)
tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate
Compound 1A-1 (3.54 g,8.49 mmol) was dissolved in methanol (50 mL), palladium on carbon (wt% = 10%,500 mg) was added, hydrogen was replaced 3 times, and the mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) overnight, filtered, and the filtrate was concentrated under reduced pressure to give a crude product of compound 1A-2, which was directly used in the next step.
Seventh step: 4- (1- (2-bromo-5- (tridentatemethoxy) -4-nitrophenyl) piperidin-4-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester (1B)
tert-butyl 4-((1-(2-bromo-5-(methoxy-d3)-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate
1A-2 (1.1 g,3.87 mmol), 1A (480 mg,3.87 mmol) and potassium carbonate (1.6 g,11.61 mmol) were mixed and dissolved in DMSO (20 mL) and stirred overnight at 100deg.C. Cooled to room temperature, extracted with 40mL of water and 100mL of ethyl acetate, and the organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane/methanol (V/V) =100/1-20/1) to give 1B (1.5 g, yield: 75%).
LCMS m/z＝516.2[M+H] +
Eighth step: 1- (Trideuteromethyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1C)
1-(methyl-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
4-Pyrazoleboronic acid pinacol ester (4 g,20.62 mmol) was dissolved in 20mL DMF, potassium carbonate (4.27 g,30.94 mmol) and deuterated iodomethane (5.98 g,41.29 mmol) were added and reacted overnight at 35 ℃. Cooled to room temperature, 40mL of water and 100mL of ethyl acetate were added for extraction, and the organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography to give 1C (2.4 g, yield: 55%).
LCMS m/z＝212.1[M+H] +
Ninth step: 4- (1- (5- (Trideuteromethoxy) -2- (1- (tridecylomethyl) -1H-pyrazol-4-yl) -4-nitrophenyl) piperidin-4-yl) methylpiperazine-1-carboxylic acid tert-butyl ester (1D)
tert-butyl 4-((1-(5-(methoxy-d3)-2-(1-(methyl-d3)-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate
To a 250mL single flask under nitrogen protection, 1B (1.37 g,2.66 mmol) and 1C (0.7 g,3.32 mmol) were added, dissolved in 100mL 1, 4-dioxane and 10mL water, then [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (270 mg,0.33 mmol) and potassium phosphate (2.12 g,10 mmol) were added thereto, nitrogen was replaced three times, reacted at 100℃for 16h, cooled to room temperature, the reaction solution was poured into water, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give 1D (1 g, yield 73%).
LCMS m/z＝521.2[M+H] +
Tenth step: 1- ((1- (5- (tridecylmethoxy) -2- (1- (tridecylmethyl) -1H-pyrazol-4-yl) -4-nitrophenyl) piperidin-4-yl) methyl) piperazine (1E)
1-((1-(5-(methoxy-d3)-2-(1-(methyl-d3)-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazine
1D (1 g,1.92 mmol) was dissolved in 10mL of dichloromethane, 3mL of trifluoroacetic acid was added and stirred at room temperature for 2h. Saturated sodium bicarbonate was quenched, extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1E (0.8 g) which was used directly in the next step.
LCMS m/z＝421.2[M+H] +
Eleventh step: 2- (2, 6-Dioxypiperidin-3-yl) -5- (4- (1- (5- (tridentatemethoxy) -2- (1- (tridentatemethyl) -1H-pyrazol-4-yl) -4-nitrophenyl) piperidin-4-yl) methyl) piperazin-1-yl) isoindole-1, 3-dione (1F)
2-(2,6-dioxopiperidin-3-yl)-5-(4-((1-(5-(methoxy-d3)-2-(1-(methyl-d3)-1H-pyrazol-4-yl)-4-nitrophenyl)piperidin-4-yl)methyl)piperazin-1-yl)isoindoline-1,3-dione
1E (0.8 g,1.90 mmol) was dissolved in 5mL DMSO, DIPEA (0.73 g,5.68 mmol) and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (0.63 g,2.28 mmol) were added and the reaction stirred at 90℃for 2h. The reaction solution was cooled to room temperature, 10mL of water was added, the solid was collected by filtration, washed with water, dissolved in DCM, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (mobile phase: DCM/MeOH (V/V) =15/1) to give 1F (0.8 g, yield: 62%).
LCMS m/z＝677.2[M+H] +
Twelfth step: 5- (4- ((1- (4-amino-5- (tridecylemethoxy) -2- (1- (tridecylemethyl) -1H-pyrazol-4-yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione (1G)
5-(4-((1-(4-amino-5-(methoxy-d3)-2-(1-(methyl-d3)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
1F (0.8G, 1.18 mmol) was dissolved in a mixture of ethanol (30 mL) and water (10 mL), reduced iron powder (1G, 17.9 mmol) and ammonium chloride (1G, 18.7 mmol) were added, reacted at 80℃for 0.5h, the reaction solution was cooled to room temperature, extracted 3 times with methylene chloride, the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1G (0.7G), which was used directly in the next step.
Thirteenth step: 5- (4- ((1- (4- ((5-bromo-4- ((4-cyclopropyl-2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-amino) -5- (tridecylmethoxy) -2- (1- (tridecylomethyl) -1H-pyrazol-4-yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 1)
5-(4-((1-(4-((5-bromo-4-((4-cyclopropyl-2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-(methoxy-d3)-2-(1-(methyl-d3)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
1G (600 mg,0.93 mmol) and 1H (450 mg,1.12 mmol) were dissolved in DMF (10 mL), and p-toluenesulfonic acid monohydrate (530 mg,2.79 mmol) was added and stirred overnight at 100 ℃. Cooling to room temperature, adding 20mL of saturated aqueous sodium bicarbonate solution, precipitating a yellow solid, suction-filtering to collect the solid, washing the filter cake with water (20 mL. Times.3), re-dissolving dichloromethane, separating the organic layer, drying over anhydrous sodium sulfate, concentrating, continuing to prepare liquid phase by preparative HPLC (instrument: waters 2767; chromatographic column: XBIdge@PrepC18 (30 mm. Times.150 mm)), purifying the mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% TFA)), concentrating the preparation, treating with dichloromethane and saturated aqueous sodium bicarbonate solution, separating the organic phase, extracting the aqueous phase with dichloromethane (30 mL. Times.3), combining the organic phases, drying over anhydrous sodium sulfate, concentrating under reduced pressure to obtain compound 1 (300 mg, yield: 32%).
LCMS m/z＝505.9[(M+2H)/2] +
1 H NMR(400MHz,D 2 O/CF 3 COOD(v/v＝1:1))δ8.23(s,1H),7.95–7.77(m,5H),7.46(s,1H),7.34(s,1H),7.31–7.17(m,2H),6.91(d,1H),5.12(dd,1H),4.23–4.06(m,2H),3.93–3.73(m,6H),3.62–3.45(m,2H),3.39–3.18(m,4H),2.98–2.86(m,2H),2.82–2.68(m,1H),2.64–2.46(m,1H),2.36–2.16(m,3H),2.11–1.86(m,9H),1.18–1.10(m,2H),0.72–0.62(m,2H).
Biological test case
Test example 1: proliferation inhibitory Activity of NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells
NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells were purchased from ATCC in the medium RPMI1640+10% FBS and DMEM+10% FBS, respectively, at 37℃with 5% CO 2 Culturing in incubator. On the first day, NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells in exponential growth phase were collected and viable cell counts were performed using an automated cell analyzer (countstar). Cell suspensions were conditioned with medium and plated in 96-well cell culture plates, 1000 cells per well NCI-H1975 (EGFR-L858R-T790M), 3000 cells per well A431. The next day, the medium was aspirated, and 90 μl fresh medium and 10 μl of different concentrations of compound were added per well, with a final DMSO concentration per well of 0.1%. At 37 ℃,5% CO 2 Culturing in incubator for 72 hr. After 72 hours of drug treatment, 50. Mu.L of CTG solution (promega, G7572) previously melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2min, and after 10min of standing at room temperature, fluorescence signal values were measured with a microplate reader (PHERAstar FSX).
Cell viability was calculated using formula V sample /V vehicle control x100% calculation. Wherein V is sample For the drug treatment group readings, V vehicle control Mean value of the solvent control group. Using origin9.2 software, an S-shaped dose-survival curve was plotted using a nonlinear regression model and IC was calculated 50 Values.
TABLE 1 results of testing compounds for proliferation inhibiting Activity on NCI-H1975 (EGFR-L858R-T790M) cells
Numbering of compounds IC50(μM)
Compound 1 0.037
Control Compound A 0.549
Control Compound B 0.658
Test Compound 1 has an inhibitory activity against A431 (EGFR-WT) cell proliferation with an IC50 of 10. Mu.M or more.
Conclusion: the compound has good proliferation inhibition activity on NCI-H1975 (EGFR-L858R-T790M) cells; has poor activity of inhibiting proliferation of A431 (EGFR-WT) cells and good selectivity.
Test example 2: mouse pharmacokinetic test
The purpose of the experiment is as follows: the test evaluates the in vivo pharmacokinetic profile and bioavailability of the test agent in mice by administering the test agent to ICR mice by single dose intravenous and intragastric administration, and determining the concentration of the test agent in the plasma of the mice.
Test animals: male ICR mice, 20-25 g. Purchased from Chengdu laboratory animal Co., ltd (SCXK (Sichuan) 2020-030).
The test method comprises the following steps: on the day of the test, ICR mice were randomized by body weight. No water is forbidden for 12-14 h1 day before administration, and feeding is recovered 4h after administration.
* Dosage is calculated as free base;
sampling: isoflurane anesthetized before and after administration, and then taken from the orbit and placed in EDTAK 2 Centrifuge tubes. The plasma was collected by centrifugation at 5000rpm at 4℃for 10 min.
Plasma collection time point for group G1: 0,5min,15min,30min,1,2,4,7,24h;
plasma collection time point for G2 group: 0,5min,15min,30min,1,2,4,7,24h;
all samples were stored at-60 ℃ prior to analytical testing. The samples were quantitatively analyzed by LC-MS/MS.
Table 2 test compound drug mice PK data (mode of administration i.g. (10 mg/kg))
Numbering of compounds AUC(ng.h.mL -1 ) T 1/2 (h)
Compound 1 78622 8.04
Control Compound B 2086 1.23
Control Compound A 563 1.54
* And (3) injection: (lavage) administration of the compound.
Conclusion: the compound synthesized by the technology has good oral absorption performance in mice, and the oral performance is superior to that of the control compounds A and B.

Claims (7)

1. A compound or a deuterated, stereoisomer, tautomer, hydrate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, the compound being selected from compounds of formula (I), wherein,
R 1a 、R 1b 、R 1c 、R 1d 、R 1e 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2f 、R 2g 、R 2h 、R 2i 、R 3 、R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f 、R 4g 、R 4h 、R 4i 、R 4j 、R 5a 、R 5b 、R 5c 、R 5d 、R 5e 、R 5f 、R 5g 、R 5h 、R 5i 、R 6a 、R 6b 、R 7a 、R 7b 、R 7c 、R 7d 、R 7e 、R 7f 、R 7g 、R 7h 、R 8a 、R 8b 、R 8c 、R 9a 、R 9b 、R 9c 、R 9d 、R 9e each independently ofAnd (3) vertical is selected from H or D, provided that at least 1 is selected from D.
2. The compound of claim 1, or a deuterated, stereoisomer, tautomer, hydrate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the following structures:
。
3. the compound according to any one of claims 1-2, or a deuterated, stereoisomer, tautomer, hydrate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, the pharmaceutically acceptable salt being selected from maleic acid, fumaric acid, hydrohalic acid (preferably hydrobromic acid and hydrochloric acid), sulfuric acid, phosphoric acid, L-tartaric acid, citric acid, L-malic acid, hippuric acid, D-glucuronic acid, glycolic acid, mucic acid, succinic acid, lactic acid, orotic acid, pamoic acid, malonic acid, gentisic acid, salicylic acid, oxalic acid or glutaric acid.
4. A pharmaceutical composition comprising a compound of any one of claims 1-3, or a deuterated, stereoisomer, tautomer, hydrate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, and a pharmaceutically acceptable carrier.
5. Use of a compound according to any one of claims 1-3 or a deuterated, stereoisomer, tautomer, hydrate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof for the manufacture of a medicament for the treatment and inhibition or degradation of BTK related diseases.
6. The use according to claim 5, wherein the disease is selected from the group consisting of tumors.
7. The use according to claim 6, wherein said tumor is selected from the group consisting of non-small cell lung cancer.
CN202310519238.4A 2022-05-18 2023-05-10 Deuterated matter for degrading EGFR and application of deuterated matter in medicine Pending CN117209538A (en)

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